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Paradigm shift in Alzheimers's research: new treatments
Date:10/15/2007

months of age. Accumulation increased significantly at the age of six months. Of all A" peptides studied, the peptide that starts with pyro-glutamate (A"N3(pE)) at position 3 showed the highest increase in accumulation in neurons by 435%.

At 10 months of age, an extensive neuronal loss (>50%) is present in the CA1/2 hippocampal pyramidal cell layer that correlates with strong accumulation of intraneuronal A" and thioflavine-S-positive intracellular material but not with extracellular A" deposits. A strong reactive astrogliosis develops together with the neuronal loss.

Cholinergic deficits

Moreover, we have studied the neuron loss in different cholinergic nuclei and found that cholinergic neurons degenerate as a function of intraneuronal A"X-42 accumulation. This finding may explain cholinergic deficits in AD patients and indicates that cholinergic dysfunction is a down-stream event in AD pathology.

In addition, complete loss of neurogenesis in the dentate gyrus in APP/PS1KI mice points to a degenerative mechanism, which is independent from intracellular A" aggregation. No intracellular A" was detected in these neurons. The reduced number of dentate gyrus neurons (-30% at six months of age) may be at least partly a function of loss of neurogenesis.

Clinical implications

  • Overall, this mouse model develops a robust neuronal dysfunction and degeneration, which triggers AD-typical changes on different levels including synaptic plasticity and working memory.

  • The neuron loss in different brain areas mostly follows the pattern of intraneuronal A"X-42 accumulation.

  • From these observations we conclude that intraneuronal A"X-42 accumulation is the major neurotoxic factor in AD etiology.

  • Of special interest is that pyro-glutamate-A"42 is the variant, which aggregates fastest in degenerating neurons. This is likely due to its enhanced s
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Contact: Thomas A. Bayer
tbayer@gwdg.de
European College of Neuropsychopharmacology
Source:Eurekalert

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